The long-term goal of this research is to identify and characterize immune correlates of protection from clinical malaria in epidemic-prone highland areas. Thirty-four million individuals are estimated to be at risk for malaria outbreaks in highland areas of East Africa. Lack of specific immune responses to P. falciparum and introduction of novel parasite genotypes may be important factors in the susceptibility of these populations to malaria outbreaks. The objective of this proposal is to determine how specific measures of immunity and P. falciparum genotype relate to risk of clinical malaria in different epidemic-prone areas. The central hypothesis of this study is that, in epidemic-prone areas, transmission intensity, age and functional antibody activity are key components of protective immunity to P. falciparum, which interact with the strain causing infection to determine clinical disease. The specific aims of this study are to: 1) determine the effect of P. falciparum transmission on antigen-specific immunity and associated protection from infection;2) identify antigen-specific immune responses protective against P. falciparum disease;and 3) elucidate the relationship of novel parasite genotype to P. falciparum disease. We will test all aims in two highland areas of Kenya with highly seasonal and sporadic transmission. We will test the first aim by comparing immune responses (IIA to MSP-119, IgG antibodies and mononuclear cell IL-4, IL-10 and IFN-g to CSP, LSA-1, TRAP, and MSP-1) between the cohorts in the two areas and comparing associated risk of new P. falciparum infection in both areas. We will test the second aim with a nested case-control study in which serum samples are obtained from the entire population in both sites and presence of immune responses is compared in individuals who do ("cases") and do not ("controls") develop malaria over the subsequent year. We will test the third aim by comparing frequency of specific genotypes in individuals presenting to the two site health centers with clinical malaria ("cases") in 1 outbreak and 3 non-outbreak months. Genotype will be determined by PCR testing for polymorphisms in 3 antigens (MSP-1, MSP-2, and GLURP) and 4 microsatellites. We anticipate that our findings will generate strategies for vaccine induction of robust immune responses against multiple antigenic variants in vulnerable populations experiencing malaria epidemics.